Mao Mao, Smith Richard S, Alavi Marcel V, Marchant Jeffrey K, Cosma Mihai, Libby Richard T, John Simon W M, Gould Douglas B
Departments of Ophthalmology and Anatomy Institute for Human Genetics, UCSF School of Medicine, San Francisco, California, United States.
The Jackson Laboratory, Bar Harbor, Maine, United States.
Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6823-31. doi: 10.1167/iovs.15-17527.
Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma.
Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves.
We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head.
Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations.
编码IV型胶原α1（COL4A1）的基因突变会导致多系统疾病，包括眼前节发育异常（ASD）和视神经发育不全。个体表型的外显率和严重程度取决于遗传背景。在此，我们在两种不同的遗传背景下测试了Col4a1突变的影响，以比较遗传背景如何影响眼部发育异常、眼压（IOP）以及青光眼的进展。
将维持在C57BL/6J背景上的Col4a1突变小鼠与129S6/SvEvTac或CAST/EiJ杂交，通过裂隙灯生物显微镜检查和光学相干断层扫描对F1代后代进行分析。我们还测量了眼压，并比较了眼睛和视神经的组织切片。
我们发现CAST/EiJ近交系对Col4a1突变的影响具有相对一致且显著的抑制作用，突变的CASTB6F1小鼠通常仅受到非常轻微的影响。相比之下，突变的129B6F1小鼠有更可变且严重的ASD和眼压调节异常，这与青光眼体征相关，包括视网膜神经节细胞轴突丢失或受损以及视神经乳头凹陷。
Col4a1突变小鼠的眼部缺陷模拟了在一部分COL4A1突变患者中观察到的ASD和青光眼。我们证明不同近交系的小鼠会出现不同程度的ASD严重程度，并且我们在携带Col4a1突变的129B6F1小鼠中检测到眼压升高和青光眼性损伤，但在CASTB6F1小鼠中未检测到。这些数据表明遗传背景差异是可能导致COL4A1突变患者中ASD和青光眼可变外显率和严重程度的一个因素。
